Cardiac α-actin over-expression therapy in dominant ACTA1 disease

Abstract

More than 200mutations in the skeletalmuscle a-actin gene (ACTA1) cause either dominant or recessive skeletal muscle disease. Currently, there are no specific therapies. Cardiac a-actin is 99% identical to skeletal muscle a-actin and the predominant actin isoform in fetal muscle. We previously showed cardiac a-actin can substitute for skeletalmuscle a-actin, preventing the early postnatal death of Acta1 knock-outmice, whichmodel recessive ACTA1 disease. Dominant ACTA1 disease is caused by the presence of 'poison' mutant actin protein. Experimental and anecdotal evidence nevertheless indicates that the severity of dominant ACTA1 disease is modulatedbytherelativeamount ofmutantskeletalmusclea-actinproteinpresent.Thus,weinvestigatedwhether transgenic over-expression of cardiac a-actin in postnatal skeletal muscle could ameliorate the phenotype of mouse models of severe dominant ACTA1 disease. In one model, lethality of ACTA1D286G. Acta11/2 mice was reduced from ~59% before 30 days of age to ~12%. In the other model, Acta1H40Y, in which ~80% ofmalemice die by 5 months of age, the cardiac a-actin transgene did not significantly improve survival. Hence cardiac aactin over-expression is likely to be therapeutic for at least some dominant ACTA1mutations. The reason cardiac a-actinwas not effective intheActa1H40Y mice is uncertain.Weshowed that theActa1H40Y mice had endogenously elevated levels of cardiac a-actin in skeletal muscles, a finding not reported in dominant ACTA1 patients. © The Author 2013.